The immune system is a complex signaling network regulated by several immune checkpoint pathways, which involve co-stimulation and co-inhibition molecules on immune cells that prevent self-reactivity and overly-activated signaling. Programmed cell death-1 protein (PD-1) is a checkpoint molecule, which inhibits T cell activity in peripheral tissues at the time of an inflammatory response to infection, thereby limiting T cell autoimmunity.
PD-1 is mainly expressed on T cells and its expression is induced during T cell activation. Besides T cells, PD-1 is also expressed on other immune cells, such as B cells, dendritic cells, natural killer cells, and macrophages. When bound by one of its ligands such as programmed death-ligand 1 (PDL1), PD-1 inhibits kinases that are involved in T cell activation, such as PI3K and AKT, through the phosphatases SHP1 and SHP2. Moreover, the engagement of PD-1:PDL1 has been shown to inhibit T cell glucose consumption, down-regulate cytokine release, and suppress T cell proliferation.
PDL1 is expressed on antigen-presenting cells (APCs) including B cells, dendritic cells, and macrophages. Moreover, PDL1 expression has been detected on various types of cancer cells, including solid tumors such as non-small-cell lung cancers (NSCLC), melanomas, breast, colon, pancreatic, gastric cancers, and hematologic malignancies such as acute myeloid leukemia, chronic lymphocytic leukemia, and others. Overexpression of PDL1 on cancer cells may lead to tumor immune evasion by increasing PD-1:PDL1 interaction, which dramatically impairs T cell function. Consistently, PDL1 expression is inversely correlated to cancer patient treatment outcomes and overall survival in clinical settings. Hence, new therapeutic agents, such as aptamers, that interfere with the PD-1:PDL1 interaction and antagonize PD-1 intracellular signaling pathways are desired.
Aptamers are short nucleic acid (DNA or RNA) molecules that are capable of forming secondary structures or even complex three-dimensional structures and have specific binding activities to target proteins. Aptamer technology has progressed tremendously since its discovery in the early 1990s. Aptamers have several advantages that make them suitable for therapeutic application, including lower molecular weight, which enables easier penetration through tissue compared to antibodies, low cost of chemical synthesis, established modification methods, and high stability. It is therefore of great interest to develop suitable aptamers having high affinity to a target protein.